Significant genetic influences on psychoactive substance use (PSU) and psychoactive substance use disorders (PSUD) have been conclusively demonstrated. An extensive body of research has also implicated a range of environmental influences on risk for PSU and PSUD. The challenge facing current researchers is to clarify the interplay between these genetic and environmental risk factors which over time can lead to the initiation and subsequent abuse/dependence of psychoactive substances. This competitive renewal requests 4 years of support for a series of detailed analyses of a unique twin data set, collection of which is now nearing completion. This sample will consist ofapproximately 750 complete adult male-male pairs, on whom extensive data has been collected in two previous interview waves. The current interview obtains, using a life-history format interview, key risk and protective factors for PSU and PSUD over 5 developmental periods (ages 8-11, 12-14, 15-17, 18-21, and 22-25). In addition, in this sample, which has essentially completed its age at risk for PSU and PSUD, we have obtained, for a second time, detailed assessments of lifetime PSU and PSUD and a lifetime calender recording key life transitions and onsets, offsets and frequency of PSU. We seek to use this rich and valuable data set to further our understanding of the development of risk for PSU and PSUD. We articulate 4 primary aims: 1. The Development of PSUD. We will identify the nature and pattern of trajectories of PSUD and related risk factors across adolescence and young adulthood, and develop a comprehensive developmental framework for PSUD by exploring the associations between genes, environment, and PSUD. 2. Contextual Factors - We will clarify the extent to which genetic and environmental risk factors for PSU and PSUD are moderated by key developmental experiences including, peer deviance and access to illicit substances. 3. Heterogeneity - Multiple subtypes of PSUD probably exist. Using the adolescent limited versus life-course persistent antisocial behavior as a paradigm, we hope to develop meaningful typologies for PSUD that will map in a useful way on the range of available etiologic factors. 4. Sequella - Given an initial episode of PSU, we will explore what predicts further use and the development of PSUD. Given the development of PSUD, we will clarify the factors that predict subsequent adult outcomes. Our research team, a combination of clinicians, statisticians and geneticists, has a long track-record of innovative and rigorous data analytic approaches to complex problems in human genetic epidemiology such as the development of PSU and PSUD.